The vitamin A derivatives termined retinoids have been proposed as chemopreventive agents for inhibiting the development of epithelial neoplasia. An important aspect of their anticarcinogenic activity may be related to their dramatic ability to modulate the differentiation of epithelial cells. There is, however, a paucity of data on the effects of retinoids on the growth and differentiation of human epithelial cells which would be the target cells for the chemopreventive activity of the retinoids. Recently, methods have been developed to culture differentiating human epidermal keratinocytes. In addition, SV-40 infected human epidermal cells which have near normal differentiation characteristics but improved growth and plating characteristics have also become available. This project will utilize these human cell culture systems to obtain a detailed knowledge of the effects of retinoids on the cell biology and biochemistry of human keratinocyte differentiation. Two-dimensional gel electrophoretic techniques will be used to characterize retinoid-induced changes in keratin and glycoprotein biosynthesis. The relationship of a retinoic acid binding protein to the effects of retinoids on human keratinocyte differentiation will also be characterized. Antagonisms or synergisms between the action of phorbol ester tumor promoters and retinoids on human keratinocytes will also be studied. Particular emphasis will be put on interactions between phorbol esters and retinoids at the level of the cell membrane. Finally, we will study the effects of retinoids on several biological and biochemical phenotypic alterations associated with virally and spontaneously transformed keratinocytes. The basic information gained from these studies should provide a fundamental basis for more rationally determinining the anticarcinogenic activity of retinoids on human cells.